The Yale Center of Research Translation (CORT) is dedicated to improving the care of patients with X linked hypophosphatemic rickets (XLH). XLH is the most common form of inherited rickets in the US and is an ideal focus for this CORT. Despite this, therapy is suboptimal and patients are burdened with significant skeletal morbidity. Recently the study of XLH has led to the identification of a novel and important phosphate (P) homeostatic system regulated in part fibroblast growth factor receptor(s). The PI and his collaborators have made important contributions to improving the care of patients with XLH as well as to our understanding of the pathogenesis of this disorder. Our expertise in this disease is demonstrated by the scope of the three proposed projects, which truly span the bedside to the bench. Project 3 provides tangible evidence of our ability to bring new discoveries to the clinic. Our scientific goal is to identify and validate mediators of skeletal disease in XLH. Project 1 will determine whether serum PTH, FGF23, or P best predict disease severity as measured by a comprehensive XLH disease index. Hyperparathyroidism is a major problem in XLH. Patients with this complication will participate in a clinical trial to determine if correcting hyperparathyroidism improves skeletal disease. Project 2 pursues our new discovery that P regulates chondrocyte apoptosis and will characterize chondrocyte P transporters and their regulation by PTH, FGF23, and vitamin D. Project 3 will identify and characterize FGF23 receptor(s). Based on these findings we will develop small molecule inhibitors of FGF23 receptor activation and demonstrate their efficacy in Hyp mice, the murine homolog of XLH. The 3 projects will interact and directly inform one another. We expect that identification of regulators of chondrocyte apoptosis (P2) will help focus the clinical investigation of biomarkers in P1. The identification of the FGF receptor in P3 will allow targeted studies of the FGF pathway in P2. The successful identification of an FGF23 inhibitor P3 will provide proof of principal for future Phase 1 clinical trials in the XLH cohort studied in P1. All projects will be supported by the Research Core. The CORT seminar series and pilot study program will better inform the Yale biomedical research community about XLH and foster new research in our Research Base. Most importantly the CORT will provide a successful working model of translational research for Yale and the wider biomedical academic community.